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Theranostics 2021; 11(2):941-957. doi:10.7150/thno.44948 This issue Cite

Research Paper

Extra-domain B of fibronectin as an alternative target for drug delivery and a cancer diagnostic and prognostic biomarker for malignant glioma

Phei Er Saw^1†, Xiaoding Xu^1†, Bo Ram Kang^3,4†, Jungsul Lee⁵, Yeo Song Lee^3,4, Chungyeul Kim⁶, Hyungsin Kim⁷, Shin-Hyuk Kang⁷, Yoo Jin Na^3,4, Hong Joo Moon⁴, Joo Han Kim⁴, Youn-Kwan Park⁴, Wonki Yoon^4,8, Jong Hyun Kim^4,8, Taek-Hyun Kwon^4,8, Chulhee Choi⁵, Sangyong Jon², Kyuha Chong^3,4,8,9✉

1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
2. Department of Biological Sciences, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
3. Photo-Theranosis and Bioinformatics for Tumor Laboratory, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
4. Department of Neurosurgery, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
5. Department of Bio and Brain Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
6. Department of Pathology, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
7. Department of Neurosurgery, Korea University Anam Hospital, Korea University Medicine, Korea University College of Medicine, 73 Goryeodae-ro, Seoungbuk-gu, Seoul, 02841, Republic of Korea
8. Neurological Institute, Korea University Guro Hospital, Korea University Medicine, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
9. Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
^†These authors contributed equally to this work.

✉ Corresponding author: Kyuha Chong. Email: kyuhajac.kr; Tel: +82-2-2626-1977; Fax: +82-2-2626-1976

Abstract

Extra-domain B of fibronectin (EDB-FN) is an alternatively spliced form of fibronectin with high expression in the extracellular matrix of neovascularized tissues and malignant cancer cells. In this study, we evaluated the practicality of using EDB-FN as a biomarker and therapeutic target for malignant gliomas (MGs), representative intractable diseases involving brain tumors.

Methods: The microarray- and sequence-based patient transcriptomic database 'Oncopression' and tissue microarray of MG patient tissue samples were analyzed. EDB-FN data were extracted and evaluated from 23,344 patient samples of 17 types of cancer to assess its effectiveness and selectivity as a molecular target. To strengthen the results of the patient data analysis, the utility of EDB-FN as a molecular marker and target for MG was verified using active EDB-FN-targeting ultrasmall lipidic micellar nanoparticles (~12 nm), which had a high drug-loading capacity and were efficiently internalized by MG cells in vitro and in vivo.

Results: Brain tumors had a 1.42-fold cancer-to-normal ratio (p < 0.0001), the second highest among 17 cancers after head and neck cancer. Patient tissue microarray analysis showed that the EDB-FN high-expression group had a 5.5-fold higher risk of progression than the EDB-FN low-expression group (p < 0.03). By labeling docetaxel-containing ultrasmall micelles with a bipodal aptide targeting EDB-FN (termed APT_EDB-DSPE-DTX), we generated micelles that could specifically bind to MG cells, leading to superior antitumor efficacy of EDB-FN-targeting nanoparticles compared to nontargeting controls.

Conclusions: Taken together, these results show that EDB-FN can be an effective drug delivery target and biomarker for MG.

Keywords: EDB-Fibronectin, Glioma, Big Data, Biomarkers, Micelles

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